The transdermal delivery of drugs, by diffusion through the epidermis, offers improvements over more traditional delivery methods, such as subcutaneous injections and oral delivery. Transdermal drug delivery avoids the hepatic first pass effect encountered with oral drug delivery. Transdermal drug delivery also reduces patient discomfort when compared to subcutaneous injection. In addition, transdermal drug delivery can provide more uniform concentrations of drug in the bloodstream of the patient over time due to the extended controlled delivery profiles of certain patches. The term "transdermal" delivery, broadly encompasses the delivery of an agent through a body surface, such as the skin, mucosa, or nails of an animal.
The skin functions as the primary barrier to the transdermal penetration of materials into the body and represents the body's major resistance to the transdermal delivery of therapeutic agents such as drugs. To date, efforts have been focussed on reducing the physical resistance, or enhancing the permeability, of the skin to the delivery of the therapeutic agent by passive diffusion. Various methods for increasing the rate of transdermal drug diffusion have been used. For example, drug-impermeable backing layers made of metal, plastic and other materials have been employed in skin patches in order to limit diffusion of drugs away from the skin, increase the hydration of the skin and, thereby, increase the rate of diffusion of drugs through the skin. Increases in the rate of absorption of agents through the skin have been produced by varying the temperature and the relative humidity of the atmosphere adjacent to the skin. Other efforts have been directed at abrading or piercing the skin by mechanically disrupting its outermost stratum corneum layer. Chemical absorption promoters (also referred to as flux enhancers or permeation enhancers) have also been utilized, both as integral components of transdermal therapeutic drug delivery devices or as a composition applied to the skin as a pretreatment step before applying the transdermal patch.
The utility of fatty acid permeation enhancers in passive transdermal drug delivery has been previously recognized (see, for example, U.S. Pat. Nos. 5,045,553 and 5,023,085 (fatty acid with additional cycloketone)). Similarly, U.S. Pat. Nos. 5,069,909 (for buprenorphine), 5,001,139 and 4,892,737 disclose the use of fatty acid esters in mixtures with other enhancers for passive transdermal delivery. More generally, C.sub.5 -C.sub.30 aliphatic monocarboxylic acids are disclosed as transdermal drug permeation enhancers in U.S. Pat. No. 4,731,241 for the passive delivery of N-ethoxycarbonyl-3-morpholino sydnonimine. U.S. Pat. No. 4,892,737 utilizes a mixture of quaternary ammonium salts with saturated and unsaturated aliphatic carboxylic acids for the passive transdermal electrotransport of agents. U.S. Pat. No. 4,882,163 passively delivers monoxidine with the aid of an alkyl aliphatic acid of at least 12 C-atoms. In U.S. Pat. No. 4,637,930, C.sub.6 -C.sub.12 fatty acid esters are used for the delivery of nicardipine hydrochloride.
A composition for the passive delivery of salicylic acid, which comprises aliphatic diols, an ester of a mono- or polyhydric alcohol and a saturated fatty acid is disclosed in published PCT patent application WO 90108507. A composition containing salicylic acid, an aliphatic 1,2-diol such as propane- or butane-diol, and a fatty oil, such as triglycerides and their fatty acid derivatives, is disclosed in published PCT patent application WO 89/00853. U.S. Pat. Nos. 4,605,670 and 5,128,376, in addition, disclose the passive percutaneous administration of an active agent in a composition containing a mixture of (1) an ester of a C.sub.7 -C.sub.18 aliphatic acid and an alcohol, a C.sub.8 -C.sub.26 aliphatic monoalcohol, or mixtures thereof, and (2) C.sub.4 -C.sub.6 cyclic amides such as pyrrolidones, and diols, triols, or mixtures thereof.
Generally, these passive methods have had only limited success in significantly increasing the transdermal flux of drug. Transdermal drug permeation rates (fluxes) can be increased over that obtained with passive diffusion by using electrically assisted transport, ie, electrotransport. The term "electrotransport" as used herein refers to delivery of an agent through a body surface (eg, skin) with the assistance of an electrical field. Electrotransport, thus, refers generally to the passage of an agent through a body surface, such as the skin, mucous membranes, or nails, which is at least partially induced by applying an electrical current through the surface. Many therapeutic agents, including drugs, may be introduced into the human body by electrotransport. The electrotransport of an agent through a body surface may be attained by one or more of several known phenomena. One widely used electrotransport phenomenon is iontophoresis, which involves the electrically induced transport of charged ions. Electroosmosis, another type of electrotransport, involves the movement of a liquid, which liquid contains one or more therapeutic agent(s) dissolved therein, through a biological membrane under the influence of an electrical field. Electroporation, still another type of electrotransport, involves the movement of an agent through transiently-created pores formed in a biological membrane under the influence of an electric field. When any given agent is electrotransported, more than one of these phenomena, including passive diffusion, may occur simultaneously to some extent. The term electrotransport, as used herein, is given its broadest possible interpretation to include the electrically induced or enhanced transport of charged species, uncharged species, or mixtures thereof, regardless of the specific mechanism(s) by which the agent(s) is(are) actually transported.
Electrotransport devices require at least two electrodes, both being in electrical contact with some portion of the skin, nails, mucous membrane, or other membrane surfaces of the body. One electrode, commonly referred to as the "donor" or "active" electrode, is the electrode from which the therapeutic agent, such as a drug or prodrug, is delivered into the body. The other electrode, typically termed the "counter" or "return" electrode, serves to close the electrical circuit through the body. For example, if a cationic (ie, a positively charged) agent is to be delivered, the anode will be the active or donor electrode while the cathode is the counter electrode. Alternatively, if the agent to be delivered is an anion (ie, a negatively charged ion) the cathode will be the donor electrode while the anode is the counter electrode. When anionic and cationic drugs need to be delivered at the same time, both the anode and cathode may be used for this purpose and the anionic drug placed in the cathode while the cationic drug is placed in the anode. In addition, electrotransport delivery devices include an electrical power source, typically in the form of one or more batteries, and optionally electrical control circuitry which regulates the flow of electric current through the electrodes and thereby the rate of drug delivery. Alternatively, the power may be supplied, at least in part, by a galvanic couple formed by contacting two electrodes made of dissimilar materials. A complete electrical circuit is formed by electrically contacting one pole of the power source to the donor electrode, the donor electrode to the body, the body to the counter electrode, and the counter electrode to the opposite pole of the power source.
The donor electrode typically includes a reservoir containing a solution of the therapeutic agent or drug to be delivered. The donor reservoir may take the form of a pouch, a cavity, a porous sponge, a pad, and a pre-formed gel body, among others. The counter electrode likewise typically includes a reservoir containing a biocompatible electrolyte salt solution. Such reservoirs are electrically connected to the anode or cathode of the electrotransport device to provide either a fixed or a renewable source of one or more therapeutic agents or drugs.
It is known that electrotransport drug flux is roughly proportional to the level of electric current applied by the device. However, there is a limit to the current density (current density is the level of electric current (mA) applied by the device divided by the skin contact area (cm.sup.2) of the electrodes) which may be comfortably tolerated by a patient. This limit on the level of current density which may be comfortably tolerated by a patient becomes more problematic as the size of the electrotransport system and, therefore, the skin contact areas of the electrodes, is reduced, ie, for electrotransport systems which are designed to be wearable. Thus, there is a limit to the level of electric current which may be applied by any electrotransport device of a given size and this current limit becomes lower as the size or the skin contact area of the device is reduced. In certain instances, electrotransport devices operating at these current limits have been unable to deliver therapeutically effective amounts of drugs. In those cases, the incorporation of a permeation enhancer into the electrotransport device may increase the amount of the agent delivered to adequate (ie, therapeutic) levels.
In the context of this application, the terms "flux enhancer" and permeation enhancers broadly describe a chemical species which either reduces the physical resistance of a body surface to the passage of an agent therethrough, alters the ionic selectivity of the body surface, increases the electrical conductivity or the permeability of the body surface, and/or the number of pathways therethrough. The use of electrotransport permeation enhancers to reduce skin resistance also helps reduce the size of the electrotransport device by requiring a reduced electrical potential (ie, voltage) to generate a particular level of electric current (ie, mA) through the skin and thereby reduce the size and/or number of batteries needed to power the device. The use of electrotransport permeation enhancers can increase the amount of drug which is electrotransported per unit of applied electric current. Therefore, electrotransport permeation enhancers can reduce the amount of current, and hence also reduce the current density applied by a device of a given size and/or reduce the size (ie, skin contact area) of the donor and counter electrodes, needed to achieve a target transdermal drug flux. A reduction in the size of, and/or current applied by, the device also improves patient comfort and a reduction in the number of batteries reduces the cost of the device.
A limited number of permeation enhancers for the electrotransport delivery of therapeutic agents have been disclosed in the literature. Ethanol has been utilized as a permeation enhancer for electrotransport delivery of polypeptides. See Srinivasan et al, J. Pharm. Sci. 79(7):588-91 (1990). In U.S. Pat. No. 4,722,726 to Sanderson et al., the skin is pretreated with an ionic surfactant (eg, sodium lauryl sulfate) to reduce competition with tissue ions migrating outwardly through the skin. Francoeur et al, U.S. Pat. No. 5,023,085 discloses the use of unsaturated C.sub.14 -C.sub.20 acids, alcohols, amines, and esters, along with ketones for the iontophoretic delivery of certain drugs. Published PCT patent application WO91/16077 discloses the use of fatty acids, such as oleic acid, lauric acid, capric acid, and caprylic acid, as permeation enhancers for the iontophoretic delivery of drugs. European Patent Application 93/300198.4 discloses delivering therapeutic agents transdermally by iontophoresis with the aid of a broadly described group of "lipid modifiers". The modifiers are generally described as having a C.sub.5 -C.sub.28 aliphatic chain and moieties such as hemiacetals amids, acetals, alcohols, carboxylic acids, esters, and others, but containing no more than 50 to 60 carbon atoms. Only a few dioxolanes, an aliphatic carbonate, and a pyrrolidone are exemplified.
A problem which arises with the addition of a permeation enhancer to the donor reservoir composition of an electrotransport device is that extraneous ions which compete with the therapeutic agent ions for transport through the body surface are introduced into the composition. For example, the addition of sodium laurate to a cationic drug-containing donor reservoir composition will have two opposing effects. The laurate ions will increase skin permeability, and hence increase the electrotransport drug delivery rate. On the other hand, the sodium ions will compete with the cationic drug for transport through the body surface and, thus, reduce the rate of electrotransport drug delivery. The sodium ions, in this context, are termed "competing ions". As used herein, this term refers to ionic species having the same (ie, same sign) charge as the therapeutic agent to be delivered by electrotransport, and which may be delivered through the body surface in its place.